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The Daily Mail
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The Daily Mail
19th June 2012
Degenerative disc disease is the subject of my thesis and is a complex subject to summarise. I have therefore simply appended the introduction from my thesis as way of an explanation.
Obviously it will take sometime to read it so as a very brief synopsis I think it is fair to say that DDD results from a complex interplay between our genetic make up and our environmental influences.
Put very simply it means that we have inherited our spines from our parents which is not really that surprising considering we inherit pretty much everything else from our parents including our ability or not to roll our tongues. Having inherited our spines from both our parents, the chances of us developing degenerative disc disease are then compounded by what we do and how we do it.
Degenerative disc disease is an established cause of low back pain and is widely believed to be an important factor in the pathogenesis of lumbar disc herniation. The socio-economic implications of low back disorders, including lifetime loss of earnings to both the individual and to the state, are well appreciated. The aetiology and pathogenesis however, has proved to be somewhat more elusive.
Degeneration is a progressive irreversible process that occurs in all connective tissues, and degenerative disc findings are known to increase with age. It has also been noted that there is considerable variation in the degree of degenerative change at any given age (Videman et al. 1995).
Early degenerative changes in the intervertebral disc include loss of hydration in the nucleus pulposus and annular tears. Both of these are associated with narrowing of the intervertebral disc space, endplate irregularities and disc herniation (Miller, Schmatz and Schultz. 1988).
Several studies (Hashizume et al. 1997; Hutton et al. 1997; Kanemoto et al. 1996) have described histochemical changes within the disc matrix with the hope of unravelling the aetiology of intervertebral disc degeneration. Additionally, the biochemical composition of the matrix has been extensively investigated. (Berthet-Colominas et al. 1982; Ghosh et al. 1977; Lyons, Eisenstein, and Sweet 1981; Piperno et al. 1997).
The variability of collagenous matrix components has also been documented and confirms evidence of the presence of collagen I in the normal annulus fibrosus, in the degenerate nucleus pulposus (NP), but not in the vertebral endplate. Collagen II and IX have been isolated in the normal NP, the inner annulus and in the endplate. Collagen III and VI have also been shown to be increased in areas of moderate to severe degeneration (Nerlich et al. 1998). Despite this, the link between pathology and aetiology still remains unknown.
In many countries, back pain is associated with occupational injury (Videman and Battie, 1999). In an injury model, the belief is that mechanical factors injure the spine. This occurs either through a single event that exceeds tissue strength, or through fatigue from repeated loading. Therefore, it may follow that the more the structural damage, the more the pain and disability. Degenerative changes include loss of hydration, annular tears, loss of disc height, endplate irregularities and disc herniation. Taking all these into consideration, it may be assumed that the stability of the motion segment will be compromised in some way, possibly leading to back pain. There are however, few clinically meaningful measures of segmental stability to support this.
In addition to this, the lack of a clear dose-response relationship between time spent in various loading conditions and degenerative findings adds considerable doubt to a causal link.
One can assume that an aetiologic factor acting systemically, will affect all spinal levels similarly. One can also hypothesise that an external mechanical factor will affect different levels of the spine differently. This is primarily due to the differential forces being transmitted at each level relating to morphological and anatomic differences. This hypothesis is based on the observation that the lower lumbar region is more commonly affected than any other (Battie et al. 1995b). Unfortunately, the degree of degeneration and range of variation seen at any age and level in an adult population suggest that disc degeneration and low back pain are a result of lifelong interactions between constitutional factors and environment (Battie et al. 1995b).
Intervertebral disc degeneration still remains the primary cause of low back pain, although the specific pathology responsible is still unknown. Several factors have been suggested in the aetiology of disc herniation and degenerative disc disease. Smoking through its effect on oxygen levels in the disc leads to increased levels of lactic acid and a reduction in disc pH. This has been shown to be detrimental to proteoglycan synthesis rates (Ohshima and Urban 1992). Changes in mechanical loading across the vertebral endplate may cause an alteration in matrix synthesis (Ishihara et al. 1996). Changes in the composition of the endplate alter the flow of nutrients to the disc (Roberts, Menage, and Urban 1989; Roberts et al. 1996).
In contrast, other authors have reported that there is no correlation between lactic acid and oxygen concentrations and age or degree of disc degeneration (Bartels et al. 1998). Although this casts doubt on the original hypothesis, it does not alter the fact that a relationship has been demonstrated and highlights the difficulty of explaining these links.
Other possible causes of low back pain include, outer annular ruptures (Moneta et al. 1994), mechanical entrapment-causing irritation of nerve roots, biochemical or immunologic reactions from substances released from the nucleus pulposus (Olmarker et al. 1995), neuropathic changes and nerve ingrowths into the degenerate disc (Freemont et al. 1997).
Taking all these possibilities into consideration and then including all the psychological and sociocultural influences it is hardly surprising that the link between the degree of physical pathology and disability is so poor.
With increasing age, histological changes in the disc have been reported (Nerlich, Schleicher, and Boos 1997; Yasuma et al. 1990) as well as biochemical abnormalities (Adams, Eyre, and Muir 1977; Antoniou et al. 1996; Liu, Roughley, and Mort 1991; Sztrolovics et al. 1999). Interestingly, degenerative disc disease is not only the preserve of the elderly and degenerative changes have been reported in patients as young as thirteen years of age (Nerlich et al. 1998).
The presence of amyloid in the intervertebral disc has also been extensively described in the literature (Athanasou et al. 1995; Ladefoged 1985). This has been attributed to ageing (Takeda et al. 1984; Yasuma, Arai, and Suzuki 1992), although amyloidal changes have also been noted from the age of fifteen (Yasuma, Arai, and Suzuki 1992).
Immunohistochemical analysis of this amyloid with antisera (anti-AA, anti-A kappa, anti-A lambda, transthyretin and beta 2-microglobulin) has yielded negative results. This suggests that it derived from an unknown precursor protein, or a new class of amyloid limited to cartilage tissue (Mihara et al. 1994; Wullbrand et al. 1990). The presence of Lysozyme in the intervertebral disc has also been previously reported and was attributed to ageing (Melrose, Ghosh, and Taylor 1989).
Studies have also associated disc degeneration with sex (Kelsey et al. 1984) (Bruske-Hohlfeld et al. 1990), intervertebral level (Miller, Schmatz, and Schultz 1988) and occupation (Videman and Battie 1999). The contribution of occupational risk factors appeared to be particularly modest however when compared to familial influences. Videman and Battie concluded that their findings reflected the combined effects of genes and early childhood environment suggesting a more complex aetiology for degenerative disc disease.
Familial studies have shown a strong predisposition to discogenic low back pain (Matsui et al. 1998; Richardson et al. 1997; Simmons et al. 1996). This is evident even taking occupation into consideration (Postacchini, Lami, and Pugliese 1988). The implication is that the aetiology of degenerative disc disease is related to both genetic and environmental factors. Twin studies have shown that disc degeneration may be explained primarily by genetic influences (Battie et al. 1995a; Sambrook, MacGregor, and Spector 1999).
Other factors, such as age and occupation, which have been among those most widely suspected of accelerating disc degeneration, have been shown to have very modest effects when compared to the effect of genetic influences (Battie et al. 1995b; Videman et al. 1997). This genetic influence is not altogether surprising, as anatomical and morphological similarities between members of the same family compared to unrelated individuals is to be expected. This is confirmed by reports demonstrating similarities in skeletal and spinal morphology in twins (King 1968; King 1971). This simple anatomical familial theory cannot solely account for the progressive changes seen in elderly identical twins. A case can be made for other mechanisms that may account for the degenerative similarities seen and several mechanisms have been suggested. These include genetic effects on the shape and size of spinal structures. This may affect mechanical properties of the spine and its subsequent vulnerability to external forces (Palmer, Stadalnick, and Arnon 1984).
It has also been postulated that the synthesis and breakdown of the biochemical and structural constituents of the disc may be genetically predetermined. This may in turn lead to accelerated disc degeneration in susceptible individuals (Battie et al. 1995b) One can speculate that specific genes may code for specific proteins in the disc. If these proteins become defective, they may lead to a structural alteration. This may in turn, lead to the formation of either smaller or larger discs. Although these discs, may appear to be functionally normal they may be mechanically more vulnerable. This may result in early degenerative disc disease.
Studies exploring genetic influences have concentrated on a number of relevant and clinically discernible entitities. These are juvenile lumbar disc herniation, familial aggregation, lumbar disc degeneration, adult lumbar disc herniation and low back pain. Identifying and examining these entities in turn, helps to justify an investigation into how much genetic information a disc is expressing at any one moment in time. This can be examined by the creation of an original representative cDNA library.
The incidence of juvenile lumbar disc herniation is usually reported as a percentage of the total number of lumbar discectomies performed. Reports from North America and Europe place the percentage between 1 to 6.6 % for patients younger than the age of 20 (Borgensen and Vang 1974; DeOrio and Bianco 1982). A higher prevalence of juvenile disc herniation has been reported in Japan. At Kobe University, 15.35 % of patients who underwent lumbar discectomy between 1951 and 1977 were under the age of 20 (Kurihara and Kataoka 1980).
There are few population-based studies on the incidence of operative intervention for juvenile disc herniation. One study of more than 75,000 Japanese secondary school children (Matsui et al. 1992) calculated the incidence rates of surgically treated lumbar disc herniae. These were 1.69 per 100,000 person-years for 10 to 12 year olds, 3.15 per 100,000 person-years for 13 to 15 year olds and 9.36 per 100, 000 person-years for 16 to 18 year olds. The mean incidence rate for all ages was 5.42 per 100,000 person-years. This compares to an incidence of 52.3 per 100,000 person-years for a population based study in adults undergoing lumbar disc surgery in Olmsted County, Minnesota between 1950 and 1979 (Bruske-Hohlfeld et al. 1990).
Sports injury or trauma is often cited as a factor in juvenile disc herniation (Epstein et al. 1984). Although injury may result in disc herniation, the incidence of cases in which trauma is a precipitating factor has been reported to be similar to that found in adults (Borgensen and Vang 1974) (Bradford and Garcia 1971).
DeOrio and Bianco in a series of 50 patients under 16 years of age found that all the children were taller than their peers. They postulated that the preponderance to disc herniation and subsequent surgery in taller adolescents might be attributable to periods of rapid growth (DeOrio and Bianco 1982).
Nelson and Janecki et al compared three different age groups of patients who had undergone lumbar discectomy. They found that younger patients were significantly more likely to have a family history of low back disorders (Nelson, Janecki, and Gildenberg 1972). This would add weight to the genetic argument, which suggests that earlier onset disease is due to a stronger genetic effect.
Further work observing familial aggregations and indications of possible genetic influences have also been reported. For example, Matsui and Tsuji et al reported a case of a 16-year-old female monozygotic twin who was admitted to hospital with low back pain and left sided radicular pain in an L5 distribution, which had been present for approximately one year. Subsequent myelography confirmed a protrusion at the L4/5 level for which the patient underwent laminotomy and discectomy. Two years later, the patient’s twin was admitted with back pain, which had been present for approximately two years and right-sided leg pain, which had been present for about 8 months. Following myelography and discography, the twin underwent laminotomy and discectomy at the L4/5 and the L5/S1 levels. The fact that lumbar disc protrusion is relatively rare in young patients and the definite lack of a history of trauma in this case, suggests that the similarity in disc pathology is not a random occurrence. Hence they concluded that genetic factors are involved in the development of juvenile herniated nucleus pulposus (Matsui, Tsuji, and Terahata 1990).
Another similar report is a case of female monozygotic twins who again presented with leg pain within a year of each other, aged 13 and 14. Computed tomography revealed a posterior bulge at the L4/5 level and a disc herniation at the L5/S1 in both girls (Gunzburg, Fraser, and Fraser 1990). As before, the onset of symptoms was very similar and neither of the girls gave any history of trauma or injury.
These two cases add weight to the argument that familial aggregation does occur. Whether it occurs more than through random occurrence, is not clear without comparison to controls. Despite this, it can be postulated that such aggregation would be extremely unlikely to occur randomly owing to the low incidence of juvenile disc herniation (Matsui et al. 1992).
Further studies investigating the degree of familial aggregation have however utilised control groups. The incidence of severe low back pain and sciatica among the parents of 63 patients under the age of 21, who had surgically treated herniation of a lumbar disc were reviewed. The parents of 63 additional patients who had non-spinal orthopaedic diagnoses were matched for age and sex with the study group, and were given the same interview. Confirmation was also sought from their medical records in an attempt to eliminate reporting bias by family members. In the group who had undergone lumbar discectomy, 32% had a positive family for that lesion. This was true for 7% in the control group. The risk of developing herniation of a lumbar disc before the age of 21 was therefore approximately five times greater in patients who have a positive family history. From this the authors concluded that there was a familial basis for herniation of a lumbar disc in patients who are less than 21 years old (Varlotta et al. 1991).
Matsui and Terahata et al studied the occurrence of lumbar disc prolapse in the parents and siblings of 40 patients who had undergone surgery for lumbar disc prolapse with 120 control patients. These were matched for age and sex. The odds ratio for surgery in a family member of a patient with juvenile disc protrusion was calculated. This was found to be greater than 5.61 times that of a family member of a patient without disc prolapse. The authors concluded that lumbar disc prolapse in patients aged 18 years or less shows familial predisposition (Matsui et al. 1992). Although both these studies used a control series to test for the degree of familial aggregation, it is recognised that family members can become affected even though the disease is not familially transmitted. In order to account for this, the risk in family members should be compared with the overall general population risk.
Matsui et al, found that 6 of 40 consecutive patients had a positive family history, yielding the odds ratio of 5.61 when combined with a baseline incidence of 5 per 100,000. This baseline was revealed from more than 75,000 children and adolescents. Varlotta et al, used matched patient-control pairs in their series of 63 disc herniations in adolescents under the age of 21. Their age-adjusted relative risk of herniation in family members of patients compared to family members of controls was 4.5, which despite differences in methods and sample populations was similar to that found by Matsui et al.
Taken together, these studies and case reports make a substantial case that juvenile disc herniation is indeed influenced by genetic factors. They do not however provide any insight into the relative contributions or the complex interactions of both genetic and environmental factors.
Lumbar disc degeneration is believed to be an important factor in the pathogenesis of lumbar disc herniation. It is therefore important to analyse the relative contributions of occupational, non-occupational and genetic factors that may influence this process.
Occupational factors believed to cause an acceleration of degenerative disc disease include accident related trauma, heavy physical loading and materials handling, including lifting, bending, and twisting (Battie, Videman et al, 1995b). Other factors cited as potential causes include prolonged sitting and sustained non-neutral work postures as well as driving (Battie, Videman et al, 1997). In all these cases occupational exposure is viewed as the primary source of mechanical insults damaging the spine, and it is assumed that without such exposure, the spine would remain healthy and back pain would not occur. If occupational factors were important causal factors resulting in disc disease, then greater exposure to occupational risk factors, should lead to greater disc degeneration.
Similarly driving has long been suspected as a cause of accelerated disc degeneration with associated back pain. It has been reported that the risk of being admitted for a disc prolapse and sciatica was lowest in professional occupations and highest in blue-collar workers and motor vehicle drivers (Kelsey and Hardy 1975). This study however was performed in the days before MRI and relied heavily on the association between disc degeneration and sciatica. Most recently a study investigating the effects of lifetime driving exposure on lumbar disc degeneration in monozygotic twins concluded that although driving may exacerbate symptoms of back pain, it does not damage the disc (Battie et al. 2002). In this study, 45 male monozygotic twins from the Finnish Twin Cohort, with very different histories of lifetime occupational driving exposure, were assessed through an extensive and structured interview. Their level of disc degeneration was assessed with lumbar magnetic resonance imaging. The authors noted that disc degeneration did not differ between occupational drivers and their twin brothers. They could not identify any overall tendency for greater disc degeneration or pathology in occupational drivers compared to their twin brothers (Battie et al. 2002). This refuted any correlation between dose and response, which would be expected.
Another study, comparing monozygotic twin siblings who had very different histories for lifetime driving, provided a rigorously controlled examination of the association between driving exposure and disc degeneration (Battie et al. 1997). No association was found.
With regard to smoking, which is thought to have a deleterious effect on the disc, it has been noted that even with an extreme smoking history (more than 30 pack years) smoking accounted for little of the variability of disc degeneration found in adults (Battie et al. 1991). This was in a study of disc degeneration in identical twins grossly discordant for smoking exposure.
In view of these findings, the authors have highlighted the genetic components of lumbar disc degeneration.
This was further highlighted by two similar studies. The first investigated the similarities in degenerative findings in the lumbar discs of 40 male identical twins (20 pairs) aged from 36 to 40. Observers were blinded to twinship and had to evaluate sagittal T1 weighted and T2 weighted magnetic resonance images with respect to changes in the endplate, desiccation of the discs, bulging or herniated discs and decrease in disc height. Similarities between co-twins were significantly greater than would be expected by chance and the authors concluded that their results were compatible with a significant genetic influence and that further investigation was warranted (Battie et al. 1995a).
In the second study, MRI’s from 115 pairs of monozygotic twins were used to estimate the effects of commonly suspected risk factors on disc degeneration. This was determined from signal intensity, disc bulging, and disc height narrowing, relative to the effects of age and familial aggregation. In their analysis of the T12-L4 region, occupational physical loading conditions accounted for 7% of the variability in disc degeneration scores among the 230 subjects. With the addition of age this rose to 16%. By adding twinship to reflect genetic influences and early-shared environment and hence familial aggregation, the degree of variability rose to 77% (Battie et al. 1995b).
The effect of familial aggregation can provide an overestimation of the role of genetic influences because twins have similar early environments and exposures during childhood and early adulthood. This may influence subsequent disc degeneration and could in part account for twin similarities. Despite this, considering the very minor effects the particular environmental factors studied had on determining disc degeneration, a strong genetic influence is suggested. The authors concluded by suggesting that disc degeneration may be primarily explained by genetic influences and as yet identified factors, which may include complex and unpredictable interactions.
In another study, the aim was to clarify whether familial predisposition for disc degeneration existed. Radiological and epidemiological methods were used in a case controlled study (Matsui et al. 1998). The incidence, level and topographical location of disc herniation, the incidence and grade of disc degeneration were observed on magnetic resonance images. Degenerative changes suggesting disc degeneration were observed on plain radiographs and compared between the relatives of patients with disc herniation (24 cases) and the controls. The controls comprised 72 age and gender matched cases that reported low back pain and/or leg pain without a family history of operated lumbar disc herniation. They found that disc degeneration in the relatives of patients who had undergone operative lumbar discectomy was significantly more severe than that in three times as many age and gender matched controls. They concluded that there might be a genetic factor in the development of lumbar disc herniation, as an expression of disc degeneration.
More recently, Sambrook et al sought to determine the extent of genetic influences on disc degeneration in a twin study using magnetic resonance imaging. They compared MRI features of degenerative disc disease in the cervical and lumbar spine of 172 monozygotic and 154 dizygotic twins, who were unselected for back pain or disc disease. Using the sum of grades, for disc height, disc bulge, osteophytosis and signal intensity at each level, an overall score for disc degeneration was calculated. From this score, heritability estimates were calculated, after adjustment for age, weight, height, smoking, occupation and physical activity. This yielded a heritability estimate of 74% in the lumbar spine and 73% in the cervical spine and the authors concluded that these results suggested an important genetic influence in intervertebral disc degeneration (Sambrook, MacGregor, and Spector 1999).
It is however, well recognised that twin studies can sometimes produce an exaggerated estimate of heritability. This is typically because of selection bias, but in this study the subjects were unaware of the hypothesis under investigation. Environmental factors common to a twin pair would also be expected to introduce bias into the heritability estimate and despite adjustment for occupational factors and smoking a certain degree of bias must be assumed.
Lumbar disc herniation with back and radicular pain is widely regarded as fairly common, however the actual incidence, resulting in surgery has been reported as 46.3 per 100,000 person-years (Bruske-Hohlfeld et al. 1990). The residents of Olmstead County, Minnesota were studied for a 30-year period from 1950 to 1979 and age and sex specific incidence rates were determined. This yielded rates of 36.0 per 100,000 person-years for women and 57.4 per 100,000 person-years for men. After adjustment, to the relative age and sex distribution for the whole of the United States, the overall incidence was calculated at 52.3 per 100,000 person-years for all lumbar spine discectomies and 46.3 per 100,000 person-years for primary procedures. The rates were noted to remain fairly constant over the study period. The investigators did distinguish between surgically proven and unproven cases of disc prolapse, and found the cumulative risk of suffering a second disc prolapse to be 8% in the next 20 years. They also noted that patients with a surgically proven lumbar disc prolapse had about 10 times the risk of requiring another surgical procedure for disc prolapse within 10 years of the first operation compared with the general population.
It should be noted however that surgical rates do vary from region to region. Although there may appear to be a clear indication for surgery in the presence of proven symptomatic disc herniation, this significant regional variation in rates of spinal surgery, clearly demonstrates that the final outcome is likely to be influenced by other factors.
As to the aetiology of lumbar disc herniation, occupations involving manual labour, vehicular vibration and simply being tall have all been implicated (Heliovaara, Knekt, and Aromaa 1987). It has also been noted that men are at greater risk of being hospitalised for disc herniation than women (Bruske-Hohlfeld et al. 1990).
Non-occupational factors, originally thought to be of aetiologic significance include height and weight, number of pregnancies and number of children, frequency of wearing shoes with high heels and smoking. Sporting activities, which were thought to be of aetiologic significance included baseball, golf, bowling, swimming, and diving, tennis, cycling or jogging. All these variables were investigated as part of an epidemiologic case controlled study to investigate risk factors for acute prolapsed intervertebral disc disease in Connecticut during 1979-1981 and found not to affect the risk for developing a prolapsed lumbar disc (Kelsey et al. 1984). The authors did however note that people in their third decade were most affected and found that among surgical cases, the ratio of men to women was 1.5 to 1.
They also observed that cigarette smoking in the past year was associated with an increased risk of disc prolapse and that the greater the number of hours spent in a motor vehicle, the greater the risk.
The possible indications of genetic influences include examples of familial aggregation. In particular, a remarkable report of the family history of a patient who underwent lumbar discectomy (Scapinelli 1993). The patient had fourteen siblings (eight men and six women), of who six (five men and one woman) had undergone lumbar discectomy. The author found that in most cases there were no obvious environmental influences. Moreover, five of the six underwent surgery in their third decade of life and some of the unoperated siblings suffered from chronic low back pain. A genetic predisposition was proposed in order to explain these findings.
Varughese and Quartey reported four brothers who had severe leg pain due to acute disc herniations and associated spinal stenosis. They all required surgery between the ages of 27 and 39. It was also noted that both parents reported similar symptoms and both underwent decompressive surgery of the lumbar spine. As a result of this, the authors concluded that the familial aggregation, together with the relatively young age at which the symptoms started, suggest that a hereditary or developmental factor may have been responsible for the pathogenesis of the spinal problems in this family.
Heikkila et al. 1989 investigated the role of genetic factors in sciatica and rates of hospital admission for lumbar discectomy. They compared pair wise concordance of monozygotic versus dizygotic twins. In this study, both hospital data and self reported data were utilised, resulting in milder cases being included. It is generally accepted that milder cases are less well reported and that severe cases are not only more accurately categorised but also more selected. Additionally, the series was large and representative with more than 9,000 same sex twins in the study.
The estimated heritability for sciatica and hospital admission was 21% and 11% respectively in this study. The reported ratio for monozygotic to dizygotic twins was however most interesting. It was noted that cases requiring hospital admission had a greater monozygotic to dizygotic ratio than cases of self reported sciatica, suggesting a greater genetic component in the more severe cases. It was also noted that the difference in the observed versus expected incidence of sciatica between monozygotic and dizygotic twins decreased with increasing age, implying that genetic influences are more significant under the age of 40.
Disc degeneration is represented by a loss of both structural and functional integrity. This may be associated with pain or discomfort. In these cases it is often referred to as disc disease.
The association between symptoms and various degenerative findings on MRI is often unclear. It has been shown that the relationship between abnormalities in the lumbar spine on MRI and low back pain is controversial (Jensen et al. 1994). Even with discographic correlation, predictive value of discogenic lumbar pain from MRI is limited (Ito et al. 1998).
Sambrook et al, 1999, when estimating heritability acknowledged that although MRI is considered the most sensitive method of assessing disc degeneration, their disc degeneration score did not necessarily reflect symptoms. However some features of disc degeneration, such as change in signal intensity or loss of disc height have been correlated with back pain (Sward et al. 1991). In view of this, it is necessary to assess the possible genetic influences on back pain.
In a study of 5,029 monozygotic and 7,876 dizygotic Swedish twin pairs, possible genetic influences on back pain that interfered with work were investigated. Back pain was identified by an affirmative answer to the specific question “have you had so much back pain during the last few years that you found it difficult to work ?” In this fairly young cohort of twins ranging from 15 to 47 years of age, 17% of males and 13% of females reported such pain. The authors viewed these findings as supportive of a relationship between genetic factors and the occurrence of pain (Bengtsson and Thorson 1991).
Normal traits and common diseases are generally polymorphic in that they have a genetic contribution from more than one gene locus. If the locus is not polymorphic, there will be no associated genetic variation. The overall genetic variation however is a result of allelic frequency. Allelic frequency is itself determined at the gene locus, with a finite number of alleles at each locus. Allele frequencies and average effects associated with the alleles determine the contribution of allelic variation. This variation can be further divided into additive genetic variance, due to gene dosage and variance due to dominance.
Monogenic diseases illustrate how, owing to a single genetic mutation, a biochemical defect can evolve and now that an increasing number of monogenic diseases have been successfully analysed down to a molecular level, the part of the gene which is indispensable for normal function can be identified. In addition to this, how phenotypes develop from different mutations can also be identified.
It is this genetic basis that is being investigated in this study, in the hope of identifying a possible genetic mutation. This could in turn be linked to the intermediate physiologic levels thereby linking genes, gene products and intermediate metabolites to biochemical and behavioural outcomes, with the ultimate aim of unravelling the contribution of genes and environment in the aetiology of the disease.
Mr Ishaque is highly experienced and widely recognised as a leading Consultant Spinal Surgeon. He is one of the few surgeons to have been awarded both the British Orthopaedic Association's Robert Jones Gold Medal and a Hunterian Professorship from The Royal College of Surgeons of England. He is one of the youngest surgeons to have achieved this, having been awarded both honours, before the age of 40.